Lung Cancer Risk in Never Smokers of European Descent is Associated with Genetic Variation in the 5P15.33 TERT-CLPTM1L Region

Abstract Introduction Inherited susceptibility to lung cancer risk in never smokers is poorly understood. The major reason for this gap in knowledge is that this disease is relatively uncommon (except in Asians), making it difficult to assemble an adequate study sample. In this study we conducted a genome-wide association study (GWAS) on the largest, to date, set of European-descent never smokers with lung cancer. Methods We conducted a two-phase (discovery and replication) GWAS in never smokers of European descent. We further augmented the sample by performing a meta-analysis with never smokers from the recent OncoArray study, which resulted in a total of 3,636 cases and 6,295 controls. We also compare our findings with those in smokers with lung cancer. Results We detected three genome-wide statistically significant SNPs rs31490 (OR 0.769, 95% confidence interval (CI) [0.722-0.820], p-value 5.31x10 -16 ), rs380286 (OR 0.770, 95% CI [0.723-0.820], p-value 4.32x10 -16 ), and rs4975616 (OR 0.778, 95% CI [0.730-0.829], p-value 1.04x10 -14 ). All three mapped to Chromosome 5 CLPTM1L-TERT region, previously shown to be associated with lung cancer risk in smokers and in never smoker Asian women, and risk of other cancers including breast, ovarian, colorectal and prostate. Conclusions We found that genetic susceptibility to lung cancer in never smokers is associated to genetic variants with pan-cancer risk effects. The comparison with smokers shows that top variants previously shown to be associated with lung cancer risk only confer risk in the presence of tobacco exposure, underscoring the importance of gene-environment interactionsin the etiology of this disease.